Angiogenesis contributes to the growth and metastasis of tumors, suggesting that agents which interfere with angiogenesis may represent an important therapeutic approach for cancer. Recent studies from our laboratory have shown that antibody or peptide antagonists to integrins alphavbeta3 and alphavbeta5 expressed on the surface of endothelial disrupt ongoing angiogenesis in several animal models in vivo leading to the regression of pre-established tumors in these animals. In fact, we developed a monoclonal antibody, directed to alphavbeta3, which has been humanized and his showing clinical benefit, without toxicity, in late stage cancer patients in a phase I clinical trial. While antibody or peptide antagonists may provide an initial proof of principle, ideally one would prefer to identify small synthetic compounds that serve as antagonists may provide an initial proof of principle, ideally one would prefer to identify small synthetic compounds that serve as antagonists of these receptors. This would allow for the development of high affinity, selective compounds with appropriate pharmacokinetic properties. Preliminary results presented in this proposal indicate it will be possible to design small organic antagonists of the integrins that have potent anti-angiogenic activity. Based on these results we now have prototypical organic compounds that will serve as a structural framework on which to design more effective and selective antagonists for these integrins. The studies outlined in this proposal are based on a close collaboration with chemists who will provide novel structures and make available targeted libraries enabling us to identify more suitable antagonists of integrins alphavbeta3 and alphavbeta5. We will incorporate a purified integrin receptor assay and cell adhesion assay to identify the most potent and selective of these compounds. These will then be tested in the chick chorioallantoic membrane model for their ability to disrupt both cytokine and tumor-induced angiogenesis. Finally, we will examine a selected number of antagonists for their ability to impact tumor growth in two murine models. Once the aims of this proposal are completed, we will have identified small molecule antagonists of integrins alphavbeta3 and alphavbeta5 that should be candidates for clinical development in cancer patients.
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